Severe Combined Immunodeficiency

Combined Immunodeficiency A talk on the Pathogenesis & Therapies For CID

Disorders of Blood & Immune SystemLecturer: Dr. Sin Yoke Min

Compiled and Presented bySu Htwe Cho, BBSF1 0707A

CIDLack of necessary immunity in the bodyDefects in production OR maturation of T cells &/or B cells of acquired immunitySusceptible to recurrent infections; esp. by Candida albicans, Steph. aureus, etc.Sterile-isolation, Immune Therapy, BM Therapy, Gene Therapy, Antibiotics.

CID - PathogenesisDirectly related to production of T and B cells of the Adaptive ImmunityMutagenic defects Metabolic deficienciesProtein Defects (DNA-binding Proteins)Eight types of immunodeficiencys Six out of 8 genetic defectsThe rest metabolic deficiencies

T cell(www.lbl.gov/Publications/Currents/Archive/Oct-03-2003.html#head0)Regulation of B Cell Development (2007)(www.tmd.ac.jp/med/mbch/projects_English.htm)

NameSpecific AbnormalityImmune DefectSusceptibility1Severe Combined Immune DeficiencyADA deficiencyNo T or B CellsGeneralPNP deficiencyNo T or B CellsGeneralX-linked SCID, c deficiencyNo T CellsGeneralAutosomal SCID,DNA repair defectNo T or B CellsGeneral2MHC Deficiency (Bare Lymphocyte Syndrome)Class I, TAP mutationsNo CD8 T CellsChronic Lung & Skin InflammationClass II, Lack of expressionNo CD4 T CellsGeneral3Wiskott-AldrichSyndromeX-Linked: Defective WASP geneDefective anti-polysaccharide & Impaired T cell activation responsesEncapsulated extracellular bacteria4X-Linked Agamma-globulinemiaLoss of Btk tyrosine kinaseNo B CellsExtracellular Bacteria, Viruses5X-Linked Lymphoproliferative SyndromeSH2D1A mutantInability to control B cell growthEBV-driven B cell tumors

Mutagenic CIDDue to mutations in genes

Autosomal Recessive ZAP-70 DeficiencyBare Lymphocyte SyndromeJAK3 DeficiencyOmenns Syndrome

X-linked XSCIDX-linked Lymphoproliferative DiseaseWiskott-Aldrich Syndrome

Cavazzana & Fisher (2007)Pike-Overzet et al. (2007)

Enzyme Deficient CIDDue to the deficiency of enzymes Deficient enzymes cause accumulation of toxic metabolic intermediates that blocks immune cell maturationTwo types of enzyme deficiencies are : ADA (Adenosine Deaminase) deficiencyPNP (Purine Nucleoside Phosphorylase) deficiency

X-linked SCIDGenes encoding portions (gamma chains) of cytokine receptors of Interleukins IL2, IL4, IL7, IL9, IL15, IL21.Interleukin Receptor protein is encoded on X chromosomeMutations in X-chromosome => XSCIDMales Descendents Affected, Females Descendents Carriers unless both parents carry mutagenic genesIL2R - Lymphocyte proliferation signaling absentIL4R - B cell class-switch defectedIL7R - Loss of antiapoptotic signal, Loss of T cell selection in Thymus IL15R - Ablation of of NK cell DevelopmentInfectious mononucleosis, X-linked lymphoproliferative disease could happen secondary to XSCIDMutagenic CIDs -Autosomal Recessive

Mutagenic CIDs X LinkedWiskott-Aldrich SyndromeAbsence of isohemagglutins & alteration of cell membrane glycoprotein sialophorin (CD43)Absence or Low IgM, Elevated IgA, Normal IgGCompromised T & B cell fuctionsFail to produce antibodies to polysaccharide antigensSmaller Lymphocytes with fewer microvilliEczema, Bloody Diarrhea, Thrombocytopenia

JAK3 DeficiencyCytokine receptors using gamma chains associate with JAK3 tyrosine kinase & major cytokine receptors transducing subunits bind to JAK1 Expression of JAK3 gene is important for lymphoid development and functionDefects in JAK3 gene could lead to defective production of lymphocytes

This 1-year-old boy was noted to have eczema and petechiae His history was significant for a subdural hematoma for which trauma Was denied; at that time the platelet count was 212,000. His diagnosis of Wiskott-Aldrich Syndrome (WAS) was confirmed by the detection of a missense mutation (Phe 128 Ser).

Fig.: The organization of the Jak homology (JH) domains of the Jak3 protein (Notarangelo and Vihinen 1999).

Bare Lymphocyte SyndromeSevere defects in both cellular and humoral immune responsesMHC Class I deficiency MHC class I molecules not expressed on lymphocyte membranesMHC Class II deficiencyLymphocytes and monocytes fail to express class II MHC antigensAgammaglobulinemia, diminshed cell-mediated immunity

Mutagenic CIDs -Autosomal Recessive

http://pathmicro.med.sc.edu/bowers/ant-pres.htm

ZAP70 DeficiencyAbsence of CD8+T cells Abundant CD3+/CD4+T lymphocytes that dont respond to TCR mediated stimuli, in peripheral bloodZAP70 is a non-src family protein tyrosine kinase necessary in T cell signalingZAP70 needed for physiologic development & function of T cellsMarked by CD8 lymphocytopenia

Mutagenic CIDs -Autosomal Recessive

www.bio.davidson.edu/courses/Immunology/Students/spring2006/Scognamiglio/Fig3.GIFwww.bio.davidson.edu/courses/Immunology/Students/spring2006/Scognamiglio/Fig4.GIF

Omenns SyndromeImmunoglobulin & TCR recombination genes : RAG (Recombination activation gene) 1 & 2 mutations Artemis Defect (VDJ rearrangement)Th2 mediated condition; Depleted B cellsElevated Serum IgE, Circulating and tissue-infiltrating T lymphocytes increasedLymph node architecture grossly abnormalCharacterized by protracted diarrhea, hepatosplenomegaly, hypereosinophiliaMutagenic CIDs -Autosomal Recessive

www.itb.cnr.it/flex/images/D.f910a9dcfd7a58b35d44/infant_omenn_syndrome.jpg

Adenosine Deaminase (ADA) Deficiency Abnormal ADA or lack of ADA couldnt bind to deoxyadenosineDeoxy-adenosine levels rise upKill T and B cells > No Adaptive Immunity PNP deficiencyPurine Nucleoside Phosphorylase DeficiencyPNP >> involved in purine degradationT & B cell development Underdeveloped thymus in infantsAutosomal Recessive

Enzyme Deficient CIDs

wikipedia/commons/c/c6/Adenosine_deaminase_1VFL.pnghttp://necat.chem.cornell.edu/Structures2/Struct_Pic2/3GGS.jpgADA Deficiency (2010)

TreatmentsBone Marrow Transplantation OR Hemopoietic Stem Cell TransplantationSomatic Gene Therapy (Retrovirus gene therapy)Passive Administration &/or transfusion of Deficient AntibodiesIntroduction of Deficient Enzymes (Adenosine Deaminase, Purine Nucleoside Phosphatase)

Plus, Antibiotics for the recurrent infections!

Treatments Various Experiments Murine ModelsIntroduction of Foreign T & B cellsSteps : Radiation Therapy kill all lymphoid cells Introduction of Immune Cells into Peripheral blood (transfusion)(3) No graft Vs. Host disease